Human HLTF mediates postreplication repair by its HIRAN domain-dependent replication fork remodelling

Nucleic Acids Research
Yathish Jagadheesh AcharLajos Haracska

Abstract

Defects in the ability to respond properly to an unrepaired DNA lesion blocking replication promote genomic instability and cancer. Human HLTF, implicated in error-free replication of damaged DNA and tumour suppression, exhibits a HIRAN domain, a RING domain, and a SWI/SNF domain facilitating DNA-binding, PCNA-polyubiquitin-ligase, and dsDNA-translocase activities, respectively. Here, we investigate the mechanism of HLTF action with emphasis on its HIRAN domain. We found that in cells HLTF promotes the filling-in of gaps left opposite damaged DNA during replication, and this postreplication repair function depends on its HIRAN domain. Our biochemical assays show that HIRAN domain mutant HLTF proteins retain their ubiquitin ligase, ATPase and dsDNA translocase activities but are impaired in binding to a model replication fork. These data and our structural study indicate that the HIRAN domain recruits HLTF to a stalled replication fork, and it also provides the direction for the movement of the dsDNA translocase motor domain for fork reversal. In more general terms, we suggest functional similarities between the HIRAN, the OB, the HARP2, and other domains found in certain motor proteins, which may explain why only a subset of DN...Continue Reading

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Citations

Jul 6, 2016·Frontiers in Genetics·Lina CipollaSimone Sabbioneda
Feb 18, 2017·Genes·Yanzhe GaoYang Yang
Apr 26, 2019·Proceedings of the National Academy of Sciences of the United States of America·Junpeng YanJacek Skowronski
Dec 28, 2018·Genes·Wendy LeungAnja-Katrin Bielinsky
Sep 28, 2018·International Journal of Molecular Sciences·Maïlyn Yates, Alexandre Maréchal
May 28, 2021·Frontiers in Cell and Developmental Biology·Shan QiuJun Huang

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Datasets Mentioned

BETA
EF442785

Methods Mentioned

BETA
PCR
X-ray
gel filtration
electrophoresis
FCS
transfection
FACS

Software Mentioned

PHASER
REFMAC5
Typhoon Trio Imager
Coot

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